The present invention relates to analogs of discodermolide and dictyostatin-1, intermediates for the synthesis of such analogs and methods of synthesis of such intermediates and analogs.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
The discovery and development of new chemotherapeutic agents for the treatment of cancer is currently of high importance. Some of the best currently available chemotherapeutic agents are natural products or natural product analogs. For example, Taxol (paclitaxel) is a natural product that is currently being used to treat patients with breast and ovarian cancer among others. A number of analogs of Taxol, including Taxotere (docetaxel), are also powerful anticancer agents.
Recently, the natural product (+)-discodermolide and its analogs have shown great promise as anticancer agents. Discodermolide has been shown to have a mechanism of action similar to Taxol but it is active against Taxol-resistant cell lines and it is more water soluble than Taxol. Accordingly, it may have a different and/or broader spectrum of action than Taxol and be easier to formulate and administer. Like Taxol, discodermolide is difficult to synthesize. Some syntheses of discodermolide are described in the following papers: Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. Total synthesis of the immunosuppressive agent (−)-discodermolide. J. Am. Chem. Soc. 1993, 115, 12621-12622; Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. Total Synthesis of (−)-Discodermolide. J. Am. Chem. Soc. 1995, 117, 12011-12012; Marshall, J. A.; Johns, B. A. Total synthesis of (+)-discodermolide. J. Org. Chem. 1998, 63, 7885-7892; Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew. Chem., Int. Ed. Eng. 2000, 39, 377-380; Paterson, I.; Florence, G. J. Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett. 2000, 41, 6935-6939; Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y. P. et al. Evolution of a gram-scale synthesis of (+)-discodermolide. J. Am. Chem. Soc. 2000, 122, 8654-8664.

Analogs of discodermolide have also been made and tested for activity. For example, see the above references and Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J. Am. Chem. Soc. 2001, 123, 9535-9544; Martello, L. A.; LaMarche, M. J.; He, L.; Beauchamp, T. J.; Smith, A. B. et al. The relationship between taxol and (+)-discodermolide: synthetic analogs and modeling studies. Chemistry Biol. 2001, 8, 843-855; Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. Total Synthesis of (−)-Discodermolide: An Application of a Chelation-Controlled Alkylation Reaction. J. Org. Chem. 1997, 62, 6098-6099; Paterson, I.; Florence, G. J. Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett. 2000, 41, 6935-6939.
Unlike Taxol, discodermolide is not readily available in large quantities from natural sources. Accordingly, assuring a sufficient supply of discodermolide is problematic. Simplified analogs that retain high anti-cancer activity but are easier to make are in urgent need.
Very recently, an unusual macrolactone natural product dictyostatin 1 has been isolated from two different sponges and a partial structure has been assigned as shown below. See Pettit, G. R.; Cichacz, Z. A. Isolation and structure of dictyostatin 1. In U.S. Pat. No. 5,430,053; 1995; Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M. Isolation and structure of the cancer cell growth inhibitor dictyostatin 1. J. Chem. Soc., Chem. Commun. 1994, 1111-1112. The configurations at C16 and C19 have not yet been assigned in the natural product and the absolute configuration is not known. Dictyostatin shows extremely high potencies against and array of cancer cell lines.

Recently, dictyostatin has also been shown to stabilize microtubules, like discodermolide and Taxol. See Wright, A. E.; Cummins, J. L.; Pomponi, S. A.; Longley, R. E.; Isbrucker, R. A. Dictyostatin compounds for stabilization of microtubules. In PCT Int. Appl.; WO62239, 2001. Accordingly, dictyostatin 1 and its analogs show great promise as new anticancer agents. There is an urgent need for a synthetic route to make dictyostatin 1 and its analogs in order to fully assign the structure of dictyostatin 1, to produce analogs to study the structure/activity relationship and to identify and produce the best possible drugs in this family.
The inventors of the present invention, as one aspect of the present invention, herein set forth a number of analogs of discodermolide, as well as methods and intermediates for the synthesis thereof. The inventors of the present invention, as another aspect of the present invention, herein set forth a family of both closed and open analogs of dictyostatin 1 with methods and intermediates for the synthesis of this family.